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Introduction

“Translation” is a bidirectional research process that often begins with the generation of scientific questions based on clinical observations and subsequently involves the application of basic scientific discoveries into patient care and the community at large. The remarkable history of hypertension-related research reflects the process of translation. The history begins with the development of devices to measure blood pressure, early descriptions of the variability of blood pressure, and recognition by the life insurance industry of the association between blood pressure level and subsequent cardiovascular disease morbidity and mortality. This background has prompted sustained laboratory research efforts aimed at understanding the physiological control of arterial pressure, identifying mechanisms of hypertension, and developing pharmacological agents for the treatment of hypertension. In turn, these initiatives have resulted in clinical trials with hypertensive patients and population-based programs with the goals of more effectively treating and preventing hypertension and its cardiovascular consequences. The purpose of this review is to summarize milestones in this ongoing translation process, a process that has had a considerable impact on patient care and reducing cardiovascular disease morbidity and mortality rates.

Blood Pressure Measurement

The history of hypertension research begins with the development of appropriate techniques for measuring blood pressure. Reverend Stephen Hales is generally credited as being the first person to measure arterial pressure, direct intra-arterial pressure in the horse in 1733. Almost a century later, sphygmographic devices were developed to measure blood pressure noninvasively in humans. The early devices were cumbersome and relatively insensitive. The introduction of the sphygmomanometer into clinical medicine in the late 1800s and early 1900s was accepted by some practitioners as a valuable aid to diagnosis. However, many were initially skeptical, and the British Medical Journal held the view that by using the sphygmomanometer “we pauperize our senses and weaken clinical acuity.”1

After Korotkoff's 1905 landmark description of the sounds associated with the appearance of the pulse wave, there was little change in the measurement of blood pressure in the first half of the 20th century. Toward the end of the 20th century, based primarily on mercury-related health concerns (which many in the field vigorously debated), the mercury manometer has essentially been replaced with aneroid and electronic devices. Mercury is still used for calibrating these devices, and standardized protocols have been recommended to assure their accuracy.

With the increased ability to measure blood pressure, the variability of blood pressure, the influence of physical and emotional stimuli, and the reduction of blood pressure during sleep were recognized by the mid-20th century. In the mid 1940s, Sir Horace Smirk2 considered it to be clinically useful to distinguish between “basal” and “casual” blood pressure. Basal blood pressure was measured after “emotional desensitization,” which, according to one protocol, consisted of an overnight fast, resting in a quiet warm room for 30 minutes, and then obtaining repeated measurements for an additional 30 minutes. Casual blood pressure consisted of the relatively stable basal blood pressure and a variable supplemental blood pressure. More recently, there has been increased recognition of the prognostic and hypertension management value of home blood pressure and ambulatory blood pressure monitoring, including the importance of day/night blood pressure differences (“dippers” versus “nondippers”).

Identification of Higher Blood Pressure as a Risk Factor

In the United States, the insurance industry provided early and consistent evidence for the clinical significance of higher blood pressures. A few companies began measuring systolic blood pressure in 1906. In 1911, the medical director of the Northwestern Mutual Life Insurance Company wrote, “The sphygmomanometer is indispensable in life insurance examinations, and the time is not far distant when all progressive life insurance companies will require its use in all examinations of applicants for life insurance.”3

As techniques for measuring blood pressure improved and increasing evidence for a blood pressure-mortality relationship became apparent, more companies began to require blood pressure measurements of insurance applicants. By 1918, companies were measuring systolic and diastolic blood pressures by auscultation, under somewhat standardized conditions, rather than simply systolic blood pressures by palpation.

In a series of reports between 1925 and 1979,4–7 the Actuarial Society of America described the population-based distribution of blood pressure, the age-related increases of blood pressure, and the relationships of blood pressure to both body size and mortality. This information was based on >10 million individuals, although data ascertainment was frequently not complete, and the duration of follow-up was relatively short, particularly in the earlier reports. Also, the earlier reports included predominantly white men.

In the 1925 report,4 among a subsample of 20 000 insured individuals, age 38 to 42 years, the distributions of systolic and diastolic blood pressures were not bimodal (Figure 1). However, this did not necessarily exclude the possibility that those individuals with higher blood pressures may have been omitted because they were denied insurance. The 1925 report also described increasing systolic and diastolic (fifth phase) blood pressures with age in >409 748 men and 51 253 women (Figure 2). At the younger ages, systolic and diastolic blood pressures were lower for women than for men. Pulse pressure also increased progressively with age in both men and women. The report also demonstrated that both systolic and diastolic blood pressures increased with increasing body size in men, defined in terms of “build groups” (average weight for each inch of height) in different age groups of men. However, the report cautioned that “the increase of blood pressure with increasing percentage of overweight is exaggerated” because of the interaction of age with weight in each age group.4 Based on limited data, the characteristics of blood pressure by body build were similar for women. “Above average” systolic and diastolic blood pressures and pulse pressure were associated with a higher mortality, the only exception being lower mortality in young adults with above average systolic blood pressures: “The ratio of deaths due to organic diseases of the heart, Bright's disease, cerebral hemorrhage, and apoplexy per 10,000 exposed to risk tended to increase with blood pressure at the older age and usually at the middle ages.”4(p52) Variations of diastolic blood pressure were of more importance than variations of pulse pressure in predicting mortality.

Systolic and diastolic blood pressures by age groups among insured individuals. Printed with permission from data compiled by Society of Actuaries, Schamburg, IL.4(pp11 and 52)

Because of changing methods for measuring blood pressure and the relatively short period of exposure, the conclusions of the 1925 report were appropriately cautious4: “(1) the mortality is lower than the average when systolic or diastolic pressure taken by itself is below the average, but no information is yet available regarding the effect of very low blood pressures; (2) the good effect of a systolic or diastolic pressure slightly below average is likely to be greater at younger than at older ages; (3) mortality increases rapidly with the increase in blood pressure over the average; and (4) substantial departures for the average blood pressure are less significant for pulse pressure than for either systolic or diastolic pressure.”

In a subsequent publication in 1939,5 the Actuarial Society of American provided more extensive information about the relationship between blood pressure and mortality. Table 1, abstracted from the 1939 report, shows the ratios of actual: expected deaths from cardiovascular and renal diseases, covering 20 210 deaths. For entry ages ≥40, systolic blood pressure was a more important predictor of death than diastolic blood pressure, and for entry ages <30 years, the influence of diastolic pressure was more marked than systolic pressure. With the exception of low systolic readings at entry ages 10 to 29 years, the prevailing tendency was an increase in mortality ratio with elevation of the systolic reading. For relatively low systolics, the mortality did not advance much as the diastolic increased, but at the middle and higher systolics, mortality mounted rapidly as diastolic readings increased. A combination of low systolic with high diastolic pressure was associated with an increased suicide rate.

Ratios of Actual: Expected Deaths From Cardiovascular and Renal Diseases, by Systolic and Diastolic Blood Pressures, Among Insured Individuals

The 1959 Build and Blood Pressure Studies again documented the increments of systolic and diastolic blood pressures with age and weight in men and women.6 That report also confirmed a sharp increase in mortality associated with relatively small increases in blood pressure. The rise in mortality was most pronounced for issue ages 30 to 59, and the rise was greater for a given increase in diastolic than for the same increase in systolic pressure. The extra mortality associated with hypertension was less for women than for men, particularly at issue ages ≥40 years.

Conclusions of a subsequent 1979 report of the Society of Actuaries were as described here.7 First, in both men and women, the mortality ratios rose with increase in blood pressure at the time of issue. Second, overweight (35% to 45% above average weight) increased mortality by 20% to 30% of normotensive and borderline hypertensive men and considerably more for men with definite high blood pressure. Increases of morality among overweight among women were “distinctly smaller” than among overweight men. Third, among insured men with “borderline” hypertension (systolic pressure 140 to 159 mm Hg and diastolic pressure 90 to 94 mm Hg), regardless of treatment, death rates from coronary disease and cerebral hemorrhage were |mF50% higher than among normotensive men. Fourth, among insured men with “definite high blood pressures” (systolic ≥160 mm Hg and/or diastolic ≥95 mm Hg), regardless of treatment, compared with normotensive men, death rates from coronary disease and cerebral hemorrhage were more than double; from hypertensive heart disease, >4 times higher; and from kidney disease, approximately double. Excess mortality from these causes increased with the rise in blood pressure. Fifth, among insured men and women treated for blood pressure before issue of their insurance whose blood pressures had been reduced to the normotensive range, the death rates from coronary disease and stroke were virtually normal.

Average blood pressures and the prevalence of both borderline and definite hypertension increased progressively with age in men and women, although, not surprisingly, hypertension prevalence in these insured individuals was considerably lower than that reported in a probability sample drawn from the general population (Health and Nutrition Examination Survey).

A potential criticism of the data in these reports is that it represents only those individuals who applied for and who were issued a life insurance policy. However, subsequent studies from the general population have corroborated and extended the basic conclusions of the insurance reports. For example, the National Health and Nutrition Examination Survey community-based surveys also describe the relationships of blood pressure with age and body size in both women and men, as well as in several racial/ethnic groups. In addition, subsequent studies describe age-related increases of blood pressure from birth to adulthood. Several large cohort studies have demonstrated that relative ranking of blood pressure during childhood tends to be maintained throughout adolescence and into adulthood, suggesting that elevated blood pressure at young ages may be a risk factor for subsequent hypertension in adulthood.8–11

In 1993, the cohort of >350 000 men screened for participation in the Multiple Risk Factor Intervention Trial confirmed a continuous and graded influence of both systolic and diastolic blood pressures on coronary heart disease mortality and end-stage renal disease, extending down to systolic blood pressures of 120 mm Hg.12 In 2001, data from the Framingham Heart Study corroborated the observation that increments in systolic or diastolic blood pressure are associated with incremental increases in mortality.13 In the Framingham study, cardiovascular disease risk increased 2.5-fold in women and 1.6-fold in men with “high normal” blood pressures (systolic blood pressure 130 to 139 mm Hg or diastolic blood pressure 85 to 90 mm Hg). In individuals over age 50 years, both the Multiple Risk Factor Intervention Trial and the Framingham study highlighted the importance of systolic blood pressure and pulse pressure for subsequent cardiovascular and renal disease. Notably, in the Multiple Risk Factor Intervention Trial, the great majority of excess deaths occurred in men with high normal blood pressures (systolic: 130 to 139 mm Hg) or with “stage 1 hypertension” (systolic: 140 to 159 mm Hg).

Although some had suggested that hypertension represented a distinct subset of the population, by 1960 Pickering14 emphasized that hypertension is a “quantitative” and not a “qualitative” trait, meaning that there is a continuous relationship between arterial pressure and mortality over the whole range of arterial pressure: “Arterial pressure is a quantity and its adverse effects are related numerically to it. The dividing line (between normal blood pressure and hypertension) is nothing more than an artifact.”

Consistent with this concept, in a 2002 meta-analysis of 61 prospective studies involving data for 1 million adults, the likelihood of “vascular mortality” (including stroke and ischemic heart disease) was directly related to a “usual” blood pressure down to at least 115/75 mm Hg.15

Because of the early descriptions of the association of body size with blood pressure, clustering of other risk factors with obesity-related hypertension has become increasingly apparent. Although there have been recent disagreements about specific criteria for a diagnosis of the “metabolic syndrome,” the constellation of related risk factors has been recognized for >80 years. In 1923, Kylin,16 a Swedish physician, described the association of hypertension with hyperglycemia and gout, and in 1947, Vague17 drew attention to the association of upper body obesity (android obesity) with type 2 diabetes mellitus and cardiovascular disease. In 1988, Raven18 described “syndrome X” as (1) resistance to insulin-stimulated glucose uptake; (2) glucose intolerance; (3) hyperinsulinemia; (4) increased very low-density lipoprotein triglycerides; (5) decreased high-density lipoprotein cholesterol; and (6) hypertension. He described relationships among these variables and suggested that insulin resistance is the basic underlying abnormality. This syndrome has been observed in many populations and in both children and adults. Defining the pathophysiology of the relationships among central obesity, insulin resistance, and hypertension continues to be an active area of laboratory and clinical research.

Evolving Concepts of the Pathophysiology of Hypertension

Recognition of the variability of blood pressure within a population and the increasing evidence for the clinical significance of higher blood pressures provoked a still-continuing search for the causes of hypertension. In 1844, Richard Bright, a physician-pathologist at Guy's Hospital in London, attributed hypertension to intrinsic renal disease. Subsequent observations by Fred Mahomed (1874), Clifford Allbutt (1896), Henri Huchard (1893), and others demonstrated that hypertension may occur without overt renal disease and may precede arteriosclerosis.19,20 Both Mahomed and Otto Frank (1911) have been credited for coining the term “essential hypertension.” This term implied that the elevation of blood pressure was a compensatory reaction to overcome ischemia of the tissue caused by constricted arterioles. In a 1912 address before the Glasgow Southern Medical Society, Sir William Osler21 made the following statement about high blood pressure associated with atherosclerosis: “In this group of cases it is well to recognize that the extra pressure is a necessity–as purely a mechanical affair as in any great irrigation system with old encrusted mains and weedy channels. Get it out of your heads, if possible, that the high pressure is the primary feature, and particularly the feature to treat.” This misinterpretation discouraged early attempts to develop drugs to lower the blood pressure.

Over time, a number of hypotheses have been proposed to explain the pathophysiology of hypertension. These hypotheses are not inherently mutually exclusive. In the late 1930s and 1940s, based on studies in experimental animals, Selye22 speculated that “stress”-induced stimulation of adrenal corticoids might contribute to clinical hypertension. According to this hypothesis, hypertension was considered a disease of adaptation to stress. Consistent with this concept, in 1974, Page23 suggested that the increase of blood pressure with age may reflect “exposure to Western civilization.” In Solomon Islands societies with low levels of acculturation, there were no age-related increases of blood pressure in both men and women. In these and other acculturated societies, historically, the occurrence of cardiovascular disease was strikingly absent. A low salt intake may have been one important environmental factor.

In 1949, Page24 introduced the concept of a “mosaic theory” to explain the etiology of hypertension (Figure 3). By this he meant that “… most of the known and probably many unknown control factors could be accommodated as long as they were in equilibrium, maintain blood pressure and tissue perfusion at relative constancy, but still adapting to tissue needs. Essential hypertension was designated a disease of control or regulation, and no constant dominant cause could be expected except in the secondary hypertensions.”24

Page's mosaic theory of hypertension. Reproduced with permission from Elsevier.24(p915)

Beginning in 1967, Guyton25 described a “hierarchy of pressure control systems” that provides both short-term damping and long-term control of arterial pressure. He hypothesized that short-term (cardiovascular reflexes) and intermediate-term (capillary fluid shifts, vascular compliance, and hormones) control mechanisms function primarily as pressure-buffering mechanisms and that long-term control of pressure is vested almost entirely in the long-term control of body fluid volumes, primarily by the kidney (Figure 4).

Guyton's model for the short-term and long-term control of arterial pressure. Reproduced with permission from Elsevier.25(p7)

In 1972, Brunner et al26 emphasized that hypertension is not a single disease but a heterogenous group of disorders with discrete etiologies. Based on the relationship of plasma renin activity to 24-hour urine sodium excretion, compared with normotensive individuals, they observed that |mF30% of hypertensives have low renin and 20% have high renin (Figure 5). This was felt to reflect 2 forms of vasoconstriction in essential hypertension, a renin angiotensin–mediated vasoconstriction (high renin) and a volume-mediated vasoconstriction (low renin). They further pointed out that patients with high renin hypertension were at greater risk for cardiovascular events than low renin patients and that the preferred therapies for high- and low-renin patients were renin-angiotensin blockers and diuretics (or calcium channel blockers), respectively.

Relationships of plasma renin activity and urine aldosterone to sodium excretion in patients with untreated essential hypertension. Reproduced with permission from The Massachusetts Medical Society.26

Mechanisms of hypertension were more readily identifiable with the discoveries of secondary forms of hypertension. Pheochromocytoma was the first known cause of curable hypertension. Frankel27 described the symptoms and the tumor of the adrenal gland in 1886, and in 1922, Labbe et al28 provided a complete description of the disease and its pathophysiology. In 1926, Roux performed the first surgical resection of a pheochromocytoma in Lausanne, Switzerland, and later in the same year Mayo performed the first surgical resection in the United States.29

Goldblatt et al30 designed a clamp to constrict the renal artery of the dog, and in 1932 he demonstrated that unilateral (and bilateral) renal artery constriction produced hypertension. Hypertension was reversed either by removal of the clamp or unilateral nephrectomy. Several decades earlier, in 1898, Tigerstedt and Bergman31 had demonstrated that the injection of a crude saline extract of rabbit kidneys into other rabbits raised the arterial pressure. They named the pressor substance in the kidney extract “renin.” It was subsequently determined that renin was the hypertension-producing factor released by the clamped, ischemic kidney. After Goldblatt's observations in the dog, physicians searched for this disorder in hypertensive patients. Clinically, most patients had either arteriosclerotic disease or, in younger patients, fibromuscular dysplasia. Based on kidney size and/or degree of narrowing of the renal artery, between 1940 and 1960, a large number of nephrectomies were performed with a low cure rate. Subsequent initiatives to evaluate the functional significance of a stenotic lesion included split-renal function tests and determination of the renal vein:renin ratio. Over time, unilateral nephrectomy was largely replaced by renal revascularization and, more recently, by stenting of the obstructed renal artery. However, with the introduction of effective antihypertensive agents, it has become apparent that hypertension can be controlled and renal function preserved in many of these patients with drug therapy. Clinical trials comparing outcomes of drug treatment with stenting or revascularization are in progress.

In 1932, Cushing32 described a group of 12 cases, all young adults, with the following clinical manifestations: rapidly acquired adiposity confined to face, neck and trunk; dusky or plethoric appearance of the skin with purplish striae; increased growth of hair on face and trunk; tendency of loss of stature and kyphosis; amenorrhea in the female and impotence in the male; raised arterial pressure; backache and abdominal pain; and fatigue and weakness. Cushing thought that all of the clinical evidence of this syndrome was caused by a small basophil adenoma of the pituitary. However, it was subsequently discovered that the pituitary disorder resulted in bilateral adrenal hyperplasia and that the clinical manifestations of the syndrome, including hypertension, were related to excess cortisol production by the adrenal stimulated by pituitary adrenocorticotropic hormone.

In 1955, Conn33 described a single patient with hypertension, muscle weakness, polyuria, and serum K +1.6 mEq/L. Electrocortin, a sodium-retaining steroid, had been identified recently in urine and renamed aldosterone. In Conn's patient, assay of the urine for this steroid was positive. Urinary 17-hydroxysteroid and 17-keto steroid excretions were normal. The right adrenal containing an adenoma was subsequently removed, and 6 months after surgery her blood pressure was 120/80 mm Hg. Continuing debate about the prevalence of primary aldosteronism depends on the intensity of screening and the selection of patient groups. In addition, we now know that ≈30% of patients with primary aldosteronism have bilateral adrenal hyperplasia rather than a discrete adrenal tumor, and these patients are generally not considered surgical candidates. Curiously, in patients with bilateral hyperplasia, hypertension may persist even after bilateral adrenalectomy.

Surgical Treatments of Essential Hypertension

For a brief period, surgical therapies were undertaken even in the absence of an identifiable secondary cause of hypertension. Based on the presumption that high pressure was attributed to overaction of the sympathetic nerves, various approaches to surgical sympathectomy were undertaken. Results of several series were reported in the late 1940s and early 1950s. Hammarstrom and Bechgaard34 and Smithwick35 reported that sympathectomy improved the expectation of life. However, as summarized by Pickering,36 “Sympathectomy has in general a limited effectiveness in reducing arterial pressure and is much Inferior to drug treatment. It can, in a few patients, have a spectacular effect. The difficulty is to know which.” Furthermore, these were painful, debilitating operations that were justified only in severe hypertension. Nevertheless, surgical sympathectomy stimulated the development of drugs that inhibited the sympathetic nervous system by blocking transmission of sympathetic nerve activity through the autonomic ganglia. In the 1950s, partial or total adrenalectomies, sometimes in combination with sympathectomy, were also carried out in selected patients with severe hypertension, and with availability of cortisone, total adrenalectomy seemed less fearful. However, these surgical procedures rapidly became superseded by the discovery and increasing availability of antihypertensive drugs.

Drug Development and Clinical Trials

Despite the increasing evidence for the association of cardiovascular disease and mortality with blood pressure, there were skeptics in the medical community and in the lay press about the imperative to lower blood pressure. In 1931, Dr Paul Dudley White, an eminent Boston cardiologist wrote: “Hypertension may be an important compensatory mechanism which should not be tampered with, even were it certain that we could control it.”36a

Also, in 1931, Hay stated in the British Medical Journal that, “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”37

In the 1946 edition of Tice's Practice of Medicine (one of the leading textbooks of Medicine at the time), Scott advised38:
May not the elevation of systemic blood pressure be a natural response to guarantee a normal circulation to the heart, brain and kidneys (“essential” hypertension). Overzealous attempts to lower the pressure may do no good and often do harm. Many cases of essential hypertension not only do not need any treatment but are much better off without it.
The earliest pharmacological remedies included nitrites, thiocyanates, dehydrogenated alkaloids of ergot, pyrogens, and veratrum viride and its extracts. By the late 1960s, the drugs most frequently used were diuretics, rauwolfia alkaloids, ganglion blockers, and sympathetic antagonists39 (Table 2). Despite increasing evidence for the risks of higher blood pressures and early clinic trial results documenting benefit of treatment, therapeutic nihilism persisted into the 1950s and 1960s.

The landmark Veterans Administration Cooperative Studies, largely designed and supervised by Dr Edward Freis, provided early clinical trial evidence for the beneficial impact of lowering blood pressure with antihypertensive agents. In a placebo-controlled trial, active drug treatment in patients with diastolic blood pressures 115 to 129 mm Hg resulted in a lower incidence of stroke, aortic dissection, and malignant hypertension within 2 years.40 Follow-up was terminated prematurely in the placebo-treated patients (15.7 versus 20.7 months in controls) because of a higher incidence of terminating events. A subsequent Veterans Administration placebo-controlled trial demonstrated the benefit of antihypertensive drug treatment of patients with diastolic blood pressures 90 to 114 mm Hg, especially patients with diastolic blood pressures ≥105 mm Hg.41 The 2 studies were published in 1967 and 1970, respectively, and the antihypertensive agents in the trials included varying combinations of reserpine, chlorothiazide, hydralazine, and guanethidine.

The design of the Veterans Affairs studies became the prototype for future clinical trials, and the results formed the basis for early recommendations for antihypertensive therapy. Table 3 lists results of representative clinical trials over the past 4 decades.42–59 Several placebo-controlled trials evaluated the benefits of antihypertensive therapy in patients with “mild” hypertension. By 1990, meta-analyses of various trials up to that time strongly supported the conclusion that lowering diastolic blood pressure with drug treatment reduced the incidence of stroke by ≈40% and fatal coronary heart disease by 15%. In the 1980s, with increasing recognition that systolic pressure is a more accurate predictor of cardiovascular events than diastolic pressure among individuals over age 50 years, several large, placebo-controlled trials focused on the impact of antihypertensive drug treatment on isolated systolic hypertension in older individuals (eg, Systolic Hypertension in the Elderly Program48 and Systolic Hypertension in Europe52). More recent trials have evaluated lower blood pressure targets for hypertension control (eg, Hypertension Optimal Treatment53). There continues to be interest in evaluating the risk:benefit ratio of lower blood pressure targets. Although most trials have not provided evidence for a J curve, at least 2 recent trials suggest that aggressively lowering blood pressure in specific high-risk patients may not be advantageous. The International Verapamil SR/Trandolapril Trial compared a verapamil-based with an atenolol-based hypertension treatment strategy in patients with coronary artery disease.59 The relationship between blood pressure and all-cause death and total myocardial infarction was J shaped, particularly for diastolic blood pressure, with a nadir at 119/84 mm Hg. In hypertensive-diabetic patients, the recent Action to Control Cardiovascular Risk in Diabetes Trial demonstrated that targeting a systolic blood pressure of <120 mm Hg, as compared with <140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events.60 Indeed, serious adverse events occurred more frequently in the lower blood pressure group (3.3% versus 1.3%; P<0.001). A trial currently in progress, the Systolic Blood Pressure Intervention Trial, is designed to test whether reducing systolic blood pressure to <120 mm Hg compared with a target of <140 mm Hg will reduce cardiovascular disease risk.

Based on pooling results from clinical trials, meta-analyses suggest essentially equivalent blood pressure–lowering effects of the following 6 major classes of drugs when used as monotherapy: diuretics, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, and α1 receptor blockers.61 However, clinical trial results have suggested that there are subgroup differences in responses (eg, diuretics for low renin patients and renin-angiotensin blockers for high renin patients). In addition, coincident with the development and increasing availability of newer antihypertensive agents in the 1970s and 1980s, trials were designed to evaluate the possibility that different classes of antihypertensive agents vary in their capacity to decrease cardiovascular and renal disease, independent of their ability to lower blood pressure. Most trials have failed to show significant differences in cardiovascular outcomes with different drug regimens, as long as equivalent decreases in blood pressure were achieved.62 However, in specific patient groups, relatively recent trial results suggest that converting enzyme inhibitors and angiotensin receptor blocking agents have advantages beyond that of blood pressure control in reducing adverse cardiovascular events in high-risk patients (eg, Heart Outcomes Prevention Evaluation,54 Losartan Intervention for Endpoint Reduction in Hypertension,56 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease58) and renal outcomes in diabetic patients.

Trials of Lifestyle Interventions

The earliest comment that relates dietary salt to blood pressure is that of Huang Ti Nei Ching Su Wein (≈2600 BC) from the translation by Wan Ping (AD 762), “… therefore if large amounts of salt are taken, the pulse will stiffen or harden.”62a In 1905, 2 French medical students, Ambard and Beaujard,63 were the first to promote the concept that the cause of hypertension was salt in the diet, and they claimed some success in reducing blood pressure by restricting salt. They thought the culprit was chloride. Chloride was readily measured by the silver nitrate method; the flame photometer had not been invented. Interest in chloride has been rekindled by the recent demonstration that sodium salts composed of anions other than chloride have relatively little impact on blood pressure.64

Subsequent attempts to restrict salt as a strategy for the treatment of hypertension met with either limited success or without careful documentation of its impact on blood pressure until the mid-1940s. In 1948, Kempner65 renewed interest in salt restriction with his introduction of the rice-fruit diet, which contained 150 mg of sodium per day. In 322 of 500 patients with hypertensive vascular disease, the diet produced one or more of the following: decrease of mean arterial pressure >20 mm Hg; reduction in heart size; reversal of T wave inversions on ECG; and disappearance of severe retinopathy. However, as described by Pickering,36 the diet did not have widespread acceptability: “It is insipid, unappetizing and monotonous and demands great care its preparation, for if the salt rises above 250 mg/d, the effect in most instances is lost.”

Over the past 25 years, a number of controlled, clinical trials have documented the benefits of reduction of salt intake, other nutritional interventions, stress reduction, weight loss, and other lifestyle modifications on the prevention and treatment of hypertension. Several of these trials are listed in Table 4.66–73

Examples of Nonpharmacologic Trials for the Prevention or Treatment of Hypertension

Basic and Translational Research

Almost a century ago, a review of the developing methodologies for measuring blood pressure and of information about blood pressure variability and its significance contained the following statement about the regulation of arterial pressure74(p9): “Blood pressure is a matter of the internal secretions … It is beyond question that one if not more of the internal secretions has the power to goad blood pressure to instant response to the cells of organs and tissues of the body for nutrition, though just how it acts is still shrouded in impenetrable mystery.”

In 1975, the National Heart, Lung and Blood Institute (NHLBI) established a Hypertension Task Force, chaired by Drs Harriet Dustan and Edward Frohlich, to assess the state of hypertension research at that time. The objectives of the task force were as follows: (1) to summarize current knowledge about mechanisms of hypertension; (2) to identify promising areas of research that were likely to result in new knowledge leading to better control and prevention of high blood pressure; and (3) to assess future research needs in the field of hypertension.

In 1979, the task force produced a 9 volume report outlining the public health problem of hypertension and identified the following research areas that merited particular emphasis75: (1) the role of sodium in the activity of vascular smooth muscle and in the regulation of fluid volumes, hormonal systems, nervous system function, and blood pressure; (2) the function of the nervous system, especially the central nervous system, in the regulation of normal arterial pressure and pathogenesis and treatment of hypertension; (3) the influence of local modulators of resistance (eg, renin-angiotensin, kallikrein-kinin, and prostaglandins) on blood pressure; (4) the role of the microcirculation and veins in the development and maintenance of hypertension; (5) the study of blood pressure regulation, hypertension, and antihypertensive therapy during growth and development of the child; (6) genetic mechanisms of hypertension; and (7) mechanisms responsible for the changes in small arteries and arterioles that cause the increase in total peripheral resistance of chronic hypertension.

The task force also developed recommendations for the use of animal models for hypertension-related research, for manpower training needs, and for resources and technology needs related to hypertension research and patient care. All of these recommendations were intended to serve as a platform for future federal funding.

The NHLBI has continued to periodically create task forces and convene working groups to develop recommendations for funding priorities for specific hypertension-related topics. For example, in 2008, the NHLBI convened a working group on target organ damage in hypertension, chaired by Drs David Harrison and Ernesto Schiffrin. The objectives were to identify new research directions that elucidate the basic biophysical and biological mechanisms underlying organ damage in hypertension and that lead to the development of preclinical and presymptomatic markers of organ damage to allow early treatment decisions with the goal of attenuating or preventing organ damage. Between 1981 and 2007, NHLBI annual support for hypertension-related research progressively increased from $80.6 million to $211.1 million. NHLBI support for years 2008, 2009, and 2010 was $167.4, $169.8, and $147.7 million, respectively. In part, a change in National Institutes of Health–wide methodology for calculating dollars associated with a particular disease may have contributed to the apparent funding decrease in 2008–2010.

As one approach to highlighting outstanding research accomplishments over the past 45 years, Table 5 lists recipients of the American Heart Association Council for High Blood Pressure Research annual award for outstanding research, beginning at the time of the introduction of this award in 1966. The purpose of the award is to recognize scientists “who have had a major impact in the field of hypertension and whose research has contributed to improved treatment and greater understanding of high blood pressure.”

Recipients of the Annual Council for High Blood Pressure Research Award for Outstanding Research

Although not the exclusive arbiter of meritorious research, the spectrum of discoveries recognized by the Council for High Blood Pressure Research over the past 4.5 decades provides an overview of the evolution of the understanding of the pathophysiology of hypertension and the application of this understanding to its treatment. Not surprisingly, perhaps reflecting the recommendations of the 1979 NHLBI Hypertension Task Force, several lines of discovery stand out, including the following: (1) neural, hormonal, renal, and vascular control of the circulation and arterial pressure; (2) identification of the components, relationships, and physiological effects of the renin-angiotensin-aldosterone system; (3) characterizations of the components and functional relationships of the sympathetic nervous system; (4) local regulation of vascular tone; (5) development of animal models to study genetic contributions and mechanisms of hypertension; (6) genetic contribution to human hypertension; and (7) delineation of the relationships of blood pressure and dyslipidemia with cardiovascular disease and stroke. Awards were also bestowed for the identification of secondary forms of hypertension and for early experiences with a nutritional intervention and with antihypertensive drug trials. A number of the more basic observations have catalyzed the development of different classes of antihypertensive drugs.

Genetic Strategies

Provoked by high heritability estimates and catalyzed by developing new technologies over the past 2 decades, including complete sequencing of the human genome in 2000 and the International HapMap Project in 2003, the search for genetic contributions to hypertension has been intense. The potential for developing new therapeutics and diagnostic tests to predict an individual's response to antihypertensive therapy is one of the motivating forces in this search. Based on evolving technologies, several strategies have been used in the search for specific hypertension-related genes. Animal models (eg, selectively bred rats, congenic rat strains, and knockout mouse models) provide powerful approaches for evaluating genetic loci and genes associated with hypertension. Comparative mapping strategies allow for the identification of syntenic genomic regions between the rat and human genome.

In humans, specific genetic variants have been identified in rare mendelian forms of hypertension; however, these variants are not applicable to the majority of patients with essential hypertension.76 Two approaches have been used to identify genetic determinants of essential hypertension, linkage analyses and association studies. Strategies in the search for blood pressure–related genes have included the study of variants in rare mendelian forms of hypertension, the investigation of candidate genes or a previously identified genetic locus, and genome-wide scans. Genome-wide association studies have been facilitated by the availability of dense genotyping chips and the International HapMap (2005–2009). Numerous genes have been studied, and genetic variants associated with essential hypertension have been identified. These include genes from the renin-angiotensin-aldosterone system, the epithelial sodium channel, the adrenergic receptor system, and α-adducin.

To date, although both candidate gene studies and genome-wide association studies have provided suggestive evidence of specific genetic contributions to blood pressure and/or hypertension, replication has been problematic. Progress has been hampered by the facts that hypertension is a polygenic disorder, different combinations of genes may influence blood pressure in a unique manner, and environmental factors affect the impact of genes on blood pressure. Future studies may move beyond DNA-based sequence approaches and involve the evaluation of heritable changes in gene expression.

Translation Into Clinical Practice and Overall Impact

Over the past several decades, there have been a number of federal initiatives to encourage translation of these scientific advances to the evaluation, treatment, and prevention of hypertension. In response to the convincing epidemiological evidence for the cardiovascular consequences of elevated blood pressure, a 1965 report of the US President's Commission on Heart Disease, Cancer, and Stroke recommended a nationwide increase in screening and treatment of high blood pressure.77 However, in the absence of evidence of the benefits of lowering blood pressure, no action was taken at that time. This evidence was provided several years later by the Veterans Administration Cooperative Studies. Consequently, in 1972, the Secretary of Health, Education, and Welfare (Elliot Richardson) charged the Director of the National Heart and Lung Institute (Dr Theodore Cooper) to develop a national plan of action. Richardson was influenced by recommendations from Mary Lasker, a long-time supporter of biomedical research and lobbyist for improving the nation's health (the Veterans Affairs Cooperative Study was supported in part by the Lasker Foundation) and Dr Michael DeBakey, a noted cardiovascular surgeon. The result was the establishment of the National High Blood Pressure Education Program (NHBPEP). The program was designed and implemented by the then US National Heart and Lung Institute to raise public awareness and stimulate blood pressure screening and treatment throughout the nation. The program evolved into a cooperative effort among professional and voluntary health agencies, state health departments, and community groups, coordinated by the NHLBI, with the overall goal to reduce death and disability related to high blood pressure through programs of professional, patient, and public education. Dr Edward Roccella served as coordinator of the program for most of its existence.

Shortly after its creation, the NHBPEP established 4 task forces, with the following objectives: (1) task force I was created to develop definitions, standards of care, and effective treatment regimens; (2) task force II was created to develop a plan for education of health professionals; (3) task force III was created to develop a program of public education; and task force IV was created to study the impact of the projected program on the existing healthcare system and assess the resources needed for full implementation of the program. Membership on the task forces included nonfederal health professionals and representatives of several federal health agencies. Reports of the task forces were published in 1973. Reflecting information available at the time, task force I recommended the following78:
A subject with a diastolic pressure of 95 mm Hg or more and/or a systolic pressure of 160 mm Hg or more should be referred for a secondary screen. At the secondary screen, the diastolic pressure should be chosen as the sole basis for recommending disposition. It is recommended that a diastolic pressure of 105 mm Hg or more be treated; a diastolic pressure below 95 mm Hg be rescreened periodically; and individual recommendations be considered for intermediate pressures.
The NHBPEP also created the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC). The initial charge to the JNC was to provide practical recommendations for the following: (1) identifying the segment of the total population with high blood pressure; (2) determining those who could be expected to benefit from antihypertensive therapy; and (3) proposing appropriate therapeutic regimens. Under the chairmanship of Dr Marvin Moser, the committee issued its first report (JNC 1) in 1977.79 Based on limited clinical trial data, recommendations in that report focused on defining hypertension in terms of blood pressure levels for initiation of drug therapy. Drug therapy was recommended for individuals with diastolic blood pressure ≥105 mm Hg. JNC 1 also recommended that blood pressures be periodically rechecked in persons with blood pressures 140/90 to 160/95 mm Hg and that treatment be individualized for patients with diastolic blood pressures from 90 to 104 mm Hg. “While recognizing the epidemiological data regarding increased risk from elevated systolic pressure at all ages … if both systolic and diastolic pressures were used as guidelines, the recommendations would be far too complex.”79 Similarly, there were no recommendations for classifying or treating systolic blood pressure in JNC II.

Over time, the JNC and various expert panels have modified clinical guidelines for defining hypertension because of better understanding of the pathophysiology, actuarial considerations of the life insurance industry, studies of blood pressure in diverse populations, consideration of the interaction of blood pressure with comorbid conditions, and the development of effective antihypertensive agents. Between 1977 and 2003, the JNC published 7 reports with recommendations for defining acceptable blood pressure levels and treatment strategies. These reports have been a critical component of the NHBPEP. The intent has been to “synthesize the available scientific evidence, and then to unify the positions of member organizations and send one clear message.”79a Each successive report has been updated based on new clinical evidence and the availability of new antihypertensive agents. The updated reports have recommended progressively more rigorous criteria for defining and treating hypertension. Table 6 lists the defining criteria in the latest JNC report (JNC VII), published in 2003.80 Although limited, increasing evidence suggests that home blood pressures and ambulatory blood pressure recordings predict target organ damage and morbid events more reliably than do clinic measurements. Recent studies have attempted to identify the “normal” blood pressure ranges for these measurements.

Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure 7 Criteria for Defining Hypertension in Adults, Age ≥18 y

Since inception of the NHBPEP, hypertension awareness, treatment, and control rates in the United States have improved (Table 7),80,81 and the age-adjusted mortality rates for stroke and coronary heart disease have declined by 57% and 63%, respectively, between 1979 and 2007 (Figure 6).82 It is likely that improved hypertension control has contributed to these favorable trends. In clinical trials of antihypertensive therapy, there has been a 35% to 40% reduction in stroke incidence, a 20% to 25% reduction of myocardial infarction, and a >50% reduction in the incidence of heart failure.82 It is likely that this remarkable success is at least partly the result of broad-based and diverse research programs supported by the federal government, pharmaceutical companies, professional societies, voluntary health agencies, and private foundations.

Age-adjusted mortality rates for coronary heart disease and stroke in the United States, 1979–2007.82

Perspectives

Despite scientific advances over the past several decades and translation of these discoveries into the clinical arena, researchers, healthcare providers, and policy-makers should not be complacent about past successes. Hypertension remains a major contributor to the global burden of disease. The worldwide prevalence is ≈26%, totaling 1 billion people.83 Because a larger proportion of the world's population is expected to be older in 2025, hypertension prevalence has been projected to increase to ≥29% by that time.84 Cardiovascular disease, including stroke, heart attack, and heart failure, is the leading cause of death and disability worldwide; elevated blood pressure accounts for 62% of stroke and 49% of coronary heart disease cases.85 Approximately 7.6 million deaths (≈13% to 15% of the total) and 92 million disability-adjusted life-years worldwide were attributable to high blood pressure in 2001.86 In the United States, hypertension prevalence remains high and hypertension control rates are unacceptably low. Currently, ≈73 million Americans have hypertension, and blood pressure is uncontrolled in 50%. Cardiovascular disease is the leading cause of mortality in the United States, accounting for ≈34% of all deaths annually.87 Building on the impact of the NHLBI Hypertension Task Force in the 1970s, this may be an appropriate time to convene a task force to recommend both future research directions and new strategies for the translation of scientific discoveries into the clinical arena.

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